Characterising the production of novel antimicrobials in Streptomyces formicae

Devine, Rebecca (2019) Characterising the production of novel antimicrobials in Streptomyces formicae. Doctoral thesis, University of East Anglia.

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Antibiotic resistance poses a major risk to modern medicine, therefore finding new antimicrobial compounds is vital. Most currently used antibiotics originate from actinomycetes discovered more than half a century ago. Previous work from the Hutchings laboratory led to the isolation of a new Streptomyces species named S. formicae from the African fungus-farming plant-ant, Tetraponera penzigi. S. formicae produces novel pentacyclic polyketides, the formicamycins, that have potent antibacterial activity against drug-resistant pathogens including methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). During this work, the genes responsible for formicamycin biosynthesis in the native producer were identified and characterised in detail using CRISPR/Cas9-mediated genome editing. In addition, we used cappable RNA- and ChIP-sequencing to determine the transcriptional organisation of the pathway and study the regulatory cascade controlling the production of- and host resistance to- these potent antimicrobials. We exploited this information to generate multiple mutants of S. formicae that overproduce formicamycins as well as various biosynthetic intermediates and shunt metabolites, some of which also have bioactivity. Attempts to understand the evolutionary origins of the biosynthetic pathway and the mode of action of these novel compounds are also presented. Furthermore, the potentiall for novel chemistry from S. formicae is not limited to the formicamycin pathway; antiSMASH analysis shows this talented strain contains at least 45 secondary metabolite biosynthetic gene clusters (BGCs). Under standard laboratory conditions, wild-type S. formicae also exhibits antifungal activity against the drug-resistant Lomentospora prolificans, and when the formicamycin BGC is deleted, the strain produces additional compounds with potent antibacterial activity against MRSA. Overall, this work demonstrates that searching under-explored environments for new species combined with genome editing is a promising route towards finding new anti-infectives.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Users 9280 not found.
Date Deposited: 15 Oct 2019 11:17
Last Modified: 10 Jun 2020 00:39


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